tbuckley/cabot-search huggingface dataset:
A subset of neutrophils as a predictive biomarker for immunotherapy response in patients with non–small-cell lung cancer and melanoma.
Authors: Yuval Shaked, Madeleine Benguigui, Ruth Halaban, Antonella Bacchiocchi, Iris Kamer, Jair Bar, Michal Lotem, Shai Shen-Orr, Mario Sznol, Tim J Cooper
Journal: Journal of Clinical Oncology (2023)

2557 Background: Despite the remarkable success of immunotherapy, only ~20-40% of cancer patients display an extended durable response. Pre-existing biomarkers for immunotherapy outcome are significantly limited in their predictive power, e.g., PDL-1 expression by tumor cells (AUC ~ 0.6-0.75). This requires additional efforts to search for new approaches to discover new biomarkers in immune-oncology. While mice are the most widely used and cost-effective model to study human disease, translating preclinical biomarkers into clinical practice faces significant obstacles – in part due to the lack of diverse or appropriate models. In this study we have taken a holistic approach to search for new biomarkers for immunotherapy outcomes, with the aim to improve translatability of the findings and their validity in cancer patients. Methods: Several pre-clinical models were used, each capturing one possible mechanistic aspect of immunotherapy response, such as tumor- and host-dependency, in order to reflect the variability seen in human cancers. These models have been analyzed for myeloid cell composition within tumors and peripheral blood using high throughput techniques such as single-cell RNA sequencing and mass cytometry, followed by rigorous bioinformatic tools. Peripheral blood mononuclear cells (PBMCs) were obtained from non-small cell lung cancer (NSCLC, n = 34) and melanoma (n = 38) patients prior to immune-checkpoint inhibitor backbone therapy as monotherapy or in combination with chemotherapy. These results were validated on additional human bulk mRNA datasets (n = 417). Results: Using the preclinical models, we identified interferon-stimulated, Ly6E hi neutrophils as a pre-treatment, blood-borne biomarker for anti-PD1 response. These results were validated in PBMCs of advanced metastatic NSCLC and malignant melanoma patients predominately treated with immune checkpoint inhibitor-based therapy, with a high degree of accuracy (AUC ~ 0.9). These results were also validated in independent cohorts of immunotherapy-treated patients with other cancer types obtained from bulk mRNA datasets including renal cell carcinoma (n = 109), urothelial carcinoma (n = 228) and additional melanoma patients (n = 80). Functional studies revealed that Ly6E hi neutrophils sensitize otherwise resistant tumors to anti-PD1 therapy, in part by directly activating cytotoxic T cells and contributing to tumor cell killing, while operate upstream of T cells in the immunotherapy response. Conclusions: Our study demonstrates a pragmatic approach to search for new, clinically relevant and functionally active cellular biomarkers for immunotherapy outcomes in humans. This study paves the way for a conceptual framework to advance the field of immuno-oncology by utilizing this approach for successful clinical trials.
Genomic alterations and self-reported Agent Orange exposure in United States veterans with metastatic prostate cancer.
Authors: JJ Haijing Zhang, Ananta Wadhwa, Adam B Weiner, Lorna Kwan, Michael J. Kelley, Karim Chamie, Kara Noelle Maxwell, Isla Garraway
Journal: Journal of Clinical Oncology (2023)

5068 Background: Agent Orange has been posited as an environmental risk factor for prostate cancer among United States Veterans. Prior studies have shown that Veterans with Agent Orange exposure are diagnosed at a younger age and at more advanced clinical stages. It is unknown if there are differences in somatic alterations among Veterans exposed to Agent Orange. Methods: Genomic alterations were identified from clinical tumor testing conducted from 2019 – 2022 in a large cohort of Veterans with metastatic prostate cancer diagnosed from 2001 – 2022. Primary prostate and metastatic carcinoma tissue specimens were submitted for Foundation Medicine tumor-only sequencing. Baseline demographics, clinical, and genomic alterations data were stratified by Veteran self-reported exposure to Agent Orange in accordance with an institutional review board approved protocol. Results: Of the 2673 Veterans with metastatic prostate cancer who underwent tumor-only genomic testing, 629 reported exposure to Agent Orange and 2044 were not exposed. After verification of military service records of Veterans with self-reported Agent Orange exposure to include only Veterans who served in the Vietnam War between 1962 – 1975 and Korean War between 1967 – 1971, 603 patients with self-reported Agent Orange exposure (22.8%) and 2044 without exposure (77.2%) were included in the analysis. On univariate analysis, TMPRSS2-ERG fusions were significantly more frequent in men who reported exposure to Agent Orange (35.3% vs 28.8%, p&lt;0.01) after multiple hypothesis testing with Benjamini-Hochberg. Agent Orange exposure also correlated to higher rates of androgen receptor ( AR) alterations (12.4% vs 9.5%, p=0.04) and FGFR1/2/3/4 alterations (3.2% vs 1.7%, p=0.02). There were no significant differences in alterations by Agent Orange exposure in TP53, CDK12, ERBB2, EGFR, BRCA, and genes implicated in the DNA damage response and repair (DDR), mismatch repair (MMR), and PTEN/PI3K/AKT pathways. On multivariable analysis controlling for race, age at diagnosis, smoking, secondary malignancies, and environment, only alterations in AR (OR 1.43, p=0.02) remained more frequent in Veterans exposed to Agent Orange. As expected, age at diagnosis (OR 0.98, p &lt;0.001) and Black/African-American race (OR 0.33, p&lt;0.001) were associated with decreased odds of TMPRSS2-ERG alterations. Conclusions: Agent Orange exposure may contribute to tumor somatic alterations in Veterans with prostate cancer. These findings hold potential prognostic and therapeutic implications for U.S. Veterans with metastatic prostate cancer. [Table: see text]
Identifying molecular targets for rational immunosuppressive strategies in patients with immune checkpoint therapy-induced myocarditis and myositis.
Authors: Bilal Ahmed Siddiqui, Nicolas Palaskas, Sreyashi Basu, Zhong He, Rahul Sheth, Maximillian Buja, Meenakshi Bhattacharjee, James Mancuso, Tihui Fu, Cezar Iliescu, Anita Deswal, Anishia Rawther-Karedath, Shalini S. Yadav, James Patrick Allison, Padmanee Sharma, Sumit Kumar Subudhi
Journal: Journal of Clinical Oncology (2023)

2511 Background: Immune checkpoint therapies (ICTs) can induce durable anti-tumor responses but also life-threatening immune-related adverse events (irAEs). Myocarditis, myositis, and myasthenia gravis (MG) are rare, often concurrent irAEs with mortality up to 40%. Steroids are the standard first-line treatment and have significant adverse events with prolonged use. We and others have identified serum autoantibodies in these irAEs, suggestive of B cell contribution to pathogenesis. Furthermore, although prior studies have shown T cells and myeloid cells in inflamed muscle tissue, their specific subtype and role in disease pathogenesis have yet to be defined. This understanding may contribute to the development of more effective immunosuppressive strategies. Hypothesis: In addition to T cells, plasma B and myeloid cells contribute to the pathogenesis of ICT-induced myocarditis, myositis, and MG. Methods: We enrolled patients with suspected ICT-induced myocarditis, myositis, and MG on an IRB-approved laboratory protocol. Diagnosis required: 1) symptoms requiring hospitalization; 2) elevated serum markers (creatine kinase ≥5x normal, troponin &gt;99th percentile or detection of autoantibodies for MG); and 3) positive biopsy, electromyography, or cardiac MRI. Patients underwent standard diagnostic testing (including endomyocardial and/or skeletal muscle biopsy) and treatment as clinically indicated. Results: 23 patients were enrolled (n=13, confirmed irAE; n=10, negative control). Most patients received combination ICT (10/13, 77%). Anti-striated muscle and/or acetylcholine receptor binding antibodies were detected in 7/13 patients (54%), including 3 without MG (known to have both T and B cell etiologies). Single cell RNA sequencing of patient tissue (confirmed irAEs: cardiac n=10, skeletal n=9; control: cardiac n=4, skeletal n=5) identified specific populations of myeloid and CD8 + T cells conserved between inflamed cardiac and skeletal muscle. Conclusions: Specific populations of T cells, myeloid cells, and plasma B cells are potential targets for rational immunosuppressive strategies in ICT-induced myocarditis and myositis and will be tested in murine models to inform future clinical trial design. [Table: see text]
Breaking down cancer costs: Hospital charges for patients with melanoma.
Authors: Henna Hundal, Kamil Taneja, Karan Patel, Alex Zhang, Michael Diaz, Sahas Chandragiri, Jules A. Cohen
Journal: Journal of Clinical Oncology (2023)

e18921 Background: 78,000 new melanoma cases are diagnosed every year in the US and many present to the emergency department (ED). Furthermore, the increasing cost of healthcare has been well established. However, there is little data on the annual trends of hospital charges and risk factors for a high charge for these patients. Methods: We utilized the 2006-2012 Nationwide Emergency Department Sample to analyze the charges of melanoma patients. Multivariate linear regressions were used to identify factors associated with higher ED and inpatient (IP) costs. The 20 most common primary diagnoses of these patients were included in the analysis to consider the reason to visit the ED. Charges were corrected for inflation by normalizing to the 2012 US Dollar. Results: Between 2006 and 2012, 239,956 melanoma patients presented to the ED. In this time period, melanoma patients were charged a total of $567,834,100 (95% Confidence Interval (CI): $519,399,100 - $616,269,100) in the ED. The average per-patient ED charge was $3,284 (95% CI: $3,152-$3,416). The per-patient ED charge increased from $2,309 (95% CI:$2,144-$2,476) in 2006 to $3,844 (95% CI:$3,638-$4,049) in 2012 (p &lt; 0.001), even after correcting for inflation. In the IP setting (57.6% of melanoma patients were admitted), melanoma patients were charged a total of $5,151,730,000 (95% CI:$4,768,685,000-$5,534,776,000). The average per-patient IP charge during this time period was $38,304 (95% CI: $36,952-$39,656). Over time, the per-patient IP charge increased from $34,591 (95% CI: $32,606-$36,576) in 2006 to $41,245 (95% CI:$39,151-$43,448) in 2012 (p &lt; 0.001), even after correcting for inflation. Table 1 shows the top 5 factors associated with higher ED and IP charges. Conclusions: The ED and IP charges associated with melanoma patients has steadily increased during this period, even after correcting for inflation. ED per-patient charges have increased by a factor of 1.7 and IP per-patient charges have increased by a factor of 1.2. Furthermore, patients that present to hospitals in the West or to a Trauma Level I center have significantly higher charges. [Table: see text]
A phase Ib/II study of intermittent talazoparib plus temozolomide in patients with metastatic castration-resistant prostate cancer (mCRPC) and no mutations in DNA damage repair (DDR).
Authors: Karen A. Autio, Christos Kyriakopoulos, Han Xiao, Hamid Emamekhoo, Daniel Costin Danila, Michael Edward Devitt, Elyn Riedel, Mehrin Jan, Howard I. Scher
Journal: Journal of Clinical Oncology (2023)

e17036 Background: Poly (ADP-ribose) polymerase (PARP) inhibition exhibits an enhanced cytotoxic effect in cancers with DDR alterations, but as monotherapy has little activity for those without DDR defects. A variety of combinatorial methods utilizing PARP inhibitors are under investigation to determine if a multimodal approach could benefit patients without DDR alterations. Supported by pre-clinical models, we hypothesized that the PARP inhibitor talazoparib in combination with the chemotherapy temozolomide could induce DNA damage leading to cell death and tumor response. Methods: This is a single arm Phase 1b/2 study of escalating doses of intermittent talazoparib (Day (D) 1-6) plus temozolomide (D2-8) in 28D cycles in patients with mCRPC without DDR mutations. Patients must have failed at least one androgen receptor signaling inhibitor and may have received chemotherapy in the hormone sensitive setting. Response is determined by a composite endpoint of overall response per RECIST v1.1, PSA50% decline, and CTC conversion from &gt;1 to 0. Pharmacokinetic samples were collected, and the mTPI-2 method was used in escalation. Results: 13 patients were enrolled across 4 dose levels in escalation. The most common adverse events were anemia (any grade (Gr) 31%, Gr3 23%), thrombocytopenia (any Gr 54%, Gr3+ 30.7%), fatigue (Gr≤2, 62%), and nausea (Gr1 46%). There was one patient with a DLT (Gr3 neutropenic fever, Gr4 thrombocytopenia). The identified RP2D was talazoparib 1 mg (D1-6) and temozolomide 75mg/m 2 (D2-8). 4 (30.8%) patients met the efficacy endpoint (3 CTC responses, 1 PR, 0 PSA50% decline). While there were no PSA50 responses, 2 (15.4%) patients had a PSA30% decline. Median duration on trial was 20 weeks with 4 (30.8%) patients on trial for ≥6mos, 2 of whom also met the efficacy endpoint. Conclusions: Hematologic toxicity was dose limiting in this combination strategy using intermittent dosing of talazoparib and temozolomide in patients with mCRPC without DDR alterations. A reduction in CTCs to 0 was identified at several dose levels, and PSA30% declines were seen in 2 patients. With identification of the RP2D, enrollment in the Phase 2 study is currently underway. Clinical trial information: NCT04019327 .
Transnational utilization of diagnostic studies across the US-Mexico border.
Authors: Fernando Cristobal Diaz, Michael Brian LaPelusa, Haydee Cristina Verduzco-Aguirre, Fernando Aldaco, Enrique Soto Pérez de Celis
Journal: Journal of Clinical Oncology (2023)

e18574 Background: Transnational healthcare utilization between US and Mexico border states is well described for specific medical conditions; however, little is known regarding the trans-border use of diagnostic imaging and invasive studies in cancer care in this region. We aimed at identifying patterns of diagnostic testing use among US- and Mexico-based patients. Methods: A cross-sectional online survey was sent to oncologists practicing in Mexican border states (Baja California, Chihuahua, Coahuila, Nuevo León, Sonora, and Tamaulipas), identified from the Mexican Society of Oncology’s member directory. The survey was administered through REDCap between October and November 2022. Responses were analyzed using descriptive statistics. The study was approved by the IRB of Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán. Results: Sixty-six respondents completed the survey. Respondents were mostly medical oncologists (n = 24) or surgical oncologists (n = 24). Most reported primarily practicing for &lt; 5 years (46.9%) in both public and private practice settings. Approximately 70% (n = 46) of respondents reported interacting with US-based patients traveling to Mexico to undergo diagnostic imaging studies, the most common of which included CT-scan (82.6%). Fifty-six percent (n = 37) of respondents interacted with patients traveling to Mexico for the purpose of undergoing invasive testing, requiring access via percutaneous puncture or incision, where the most frequently sought test included a biopsy (91.9%, n = 34). Forty percent (n = 26) of respondents interacted with patients from Mexico who travelled to the US for diagnostic imaging, who most frequently sought nuclear imaging studies (80.0%). Approximately 33% of respondents (n = 22) interacted with patients who travelled for diagnostic testing, with next generation sequencing (NGS) the most common study requested (90.9%). See Table. Conclusions: Diagnostic studies play an essential role in the management of cancer. A significant proportion of patients travelling to Mexico for diagnostic tests pursued CT imaging scans and biopsies, which may be due to the lower costs of those procedures in Mexico, even for patients who might have insurance. In contrast, most Mexican patients who traveled to the US for testing pursued nuclear imaging and NGS, perhaps reflecting lack of access and availability. Strategies aimed at improving access to evidence-based diagnostic testing are needed to reduce inequities both in high- and middle-income countries. [Table: see text]
Survival outcomes with CPX-351 vs 7+3 by baseline bone marrow blast percentage in older adults with newly diagnosed high-risk or secondary acute myeloid leukemia: A 5-year follow-up study.
Authors: Ellen K. Ritchie, Tara L. Lin, Laura F. Newell, Robert K. Stuart, Scott R. Solomon, Richard M. Stone, Gary J. Schiller, Matthew Joseph Wieduwilt, Eileen A. Ryan, Nalina Dronamraju, Jeffrey E. Lancet, Jorge E. Cortes
Journal: Journal of Clinical Oncology (2023)

7027 Background: CPX-351, a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio, is approved for newly diagnosed therapy-related acute myeloid leukemia (AML) or AML with myelodysplasia-related changes in the US and Europe following positive efficacy and safety data from the pivotal phase 3 clinical trial (NCT01696084). A previous exploratory analysis of the trial data (median follow-up 20.7 months) showed improved survival outcomes with CPX-351 vs conventional 7+3 chemotherapy in adults with newly diagnosed high-risk or secondary AML (sAML) irrespective of baseline bone marrow (BM) blast percentage. Here we report 5-year follow-up data (median follow-up 60.9 months) to provide insights into the longer-term efficacy and safety of CPX-351 in these patient subgroups. Methods: Patients (60–75 years) with a pathologic diagnosis of AML (high-risk/sAML) per the WHO 2008 criteria (≥20% blasts in peripheral blood or BM) and an ECOG PS of 0–2 were randomized to receive CPX-351 or 7+3 chemotherapy. In these post hoc subgroup analyses at 5 years follow-up, overall survival (OS), event-free survival (EFS) and complete remission (CR) were assessed by baseline BM blast percentage. The analysis included patients with low ( &lt; 20%) BM blasts to account for changes in blast count thresholds in the updated WHO AML classification. Results: Overall, median OS and EFS were longer with CPX-351 vs 7+3 in each subgroup; median OS was greatest in low blast subgroups for both treatments (Table). Higher CR rates were observed with CPX-351 vs 7+3 irrespective of baseline BM blasts. Median Kaplan-Meier (KM)-estimated survival rates increased with CPX-351 vs 7+3 across BM blast subgroups. The CPX-351 safety profile was comparable across BM blast subgroups and consistent with the known safety profile of 7+3. Conclusions: These 5-year follow-up data suggest that CPX-351 results in improved outcomes irrespective of baseline BM blast percentage vs conventional 7+3 chemotherapy in older adults with AML. Clinical trial information: NCT01696084 . [Table: see text]
Treatment patterns and outcomes among locally advanced cervical cancer patients receiving concurrent chemoradiotherapy.
Authors: Francesca Coutinho, Mugdha Gokhale, Charlotte Doran, Matthew Monberg, Karin Sayuri Yamada, Lei Chen
Journal: Journal of Clinical Oncology (2023)

e17511 Background: Concurrent chemoradiotherapy (CCRT) is standard treatment for patients with locally advanced cervical cancer (LACC). However, little is known on the real-world treatment patterns and outcomes among LACC patients. This study evaluated patient characteristics and treatment patterns of LACC patients, and real-world outcomes among patients receiving CCRT as the first treatment after diagnosis (CCRT-first) in US academic and community settings. Methods: Data were drawn from the ConcertAI Oncology Dataset, a US-based electronic medical record dataset. We included adult patients diagnosed between 2010-2018 with LACC, defined as stage IB2-IIB with node involvement or stage III-IVA cervical cancer, with squamous cell carcinoma (excl. verrucous), adenocarcinoma (excl. clear cell and endometroid), or adenosquamous carcinoma. Patients with prior immunotherapy or a second primary cancer (other than in situ or non-melanoma skin cancer) were excluded. Patients were followed from initial diagnosis through end of the second regimen of systemic anti-cancer therapy, end of record, or death, whichever occurred first. Patient characteristics and treatments were reported overall and in CCRT-first patients. Among CCRT-first patients, real-world time on CCRT treatment (rwTOT), recurrence-free survival (rwRFS), and progression-free survival (rwPFS) among patients with persistent disease were estimated using Kaplan-Meier methods. Results: Overall, 300 patients with LACC were included. At LACC diagnosis, median age of patients was 51 years, 53.7% were White, 30.0% were Black, 48.0% were peri/postmenopausal, 89.3% had squamous cell histology, 75.3% had stage III disease, 92.7% had no evidence of performance status impairment, 50.3% were treated in community settings, and 21.7% had only public insurance (11.0% Medicaid, 10.7% Medicare; 56.3% had no documentation of insurance). Distributions were similar among CCRT-first patients. First treatment after diagnosis included CCRT (N=229), surgery (N=28), systemic therapy (N=11), and radiation therapy alone (N=5). 27 were untreated, and 29 patients received CCRT after another therapy. Of the 229 CCRT-first patients, median (95% CI) rwTOT was 1.6 (1.4-1.7) months; 78.2% received cisplatin within CCRT, and median duration of cisplatin treatment was 35 days; 28.4% received a systemic therapy after CCRT, and 11.8% further initiated a second systemic therapy. 27 patients had recurrent disease after complete response (median rwRFS not reached). 179 patients had persistent disease after CCRT, among whom median (95% CI) rwPFS was 29.7 (16.9-59.3) months from CCRT start. Conclusions: In US clinical practice during 2010-2018, most LACC patients received CCRT as the first treatment after diagnosis. The high proportion of patients who develop persistent disease after CCRT indicates a need for improved first treatment options.